1  2201 117 EPIGENETIC MODIFICATION OF GLUCOCORTICOID RECEPTOR PROMOTER I(7) IN MATERNALLY SEPARATED AND RESTRAINT-STRESSED RATS. GLUCOCORTICOID RECEPTOR (GR) PROMOTER I(7) IS SUSCEPTIBLE TO EPIGENETIC CHANGES INDUCED BY ENVIRONMENTAL INFLUENCES. EARLY LIFE STRESS (ELS) HAS A PERSISTENT IMPACT ON GR EXPRESSION, AS WELL AS BEHAVIOR, IN ADULT RODENTS VIA EPIGENETIC CHANGES OF GR PROMOTER I(7). MOREOVER, VARIOUS STRESSORS CAN INDUCE HISTONE MODIFICATIONS IN THIS REGION DURING ADULTHOOD. THUS, THE PRESENT STUDY AIMED TO INVESTIGATE WHETHER MATERNALLY SEPARATED (MS) RATS EXPOSED TO CHRONIC RESTRAINT STRESS (RS) WOULD EXHIBIT HISTONE MODIFICATIONS OF GR PROMOTER I(7) IN THE HIPPOCAMPUS. RATS WERE SUBJECTED TO MS (3H PER DAY) ON POSTNATAL DAYS (PND) 1-21. THEN, DURING ADULTHOOD (PND 56-77), THE RATS WERE EXPOSED TO RS (2H PER DAY) FOLLOWED BY TREATMENT WITH ESCITALOPRAM (10MG/KG). THE MS AND RS GROUPS EXHIBITED SIGNIFICANT DECREASES IN TOTAL AND EXON I(7) GR MRNA LEVELS AND THE COMBINATION OF MS AND RS EXERTED A GREATER EFFECT ON THESE MRNA LEVELS THAN EITHER MS OR RS ALONE. ADDITIONALLY, BOTH THE MS AND RS GROUPS SHOWED SIGNIFICANT REDUCTIONS IN HISTONE H3 ACETYLATION AT GR PROMOTER I(7) AND THE COMBINATION OF MS AND RS HAD A GREATER EFFECT THAN DID EITHER MS OR RS ALONE. CHRONIC ESCITALOPRAM TREATMENT AMELIORATED THESE CHANGES. THE PRESENT RESULTS INDICATE THAT POSTNATAL MS AND ADULT RS INFLUENCE GR EXPRESSION THROUGH HISTONE MODIFICATION AT GR PROMOTER I(7), AND THAT THE COMBINATION OF THE TWO STRESSORS POTENTIATES THESE CHANGES. FURTHERMORE, EPIGENETIC MECHANISMS ARE INVOLVED IN ESCITALOPRAM ACTION.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
2  1751  68 EARLY LIFE STRESS INCREASES STRESS VULNERABILITY THROUGH BDNF GENE EPIGENETIC CHANGES IN THE RAT HIPPOCAMPUS. EARLY LIFE STRESS (ELS) EXERTS LONG-LASTING EPIGENETIC INFLUENCES ON THE BRAIN AND MAKES AN INDIVIDUAL SUSCEPTIBLE TO LATER DEPRESSION. IT IS POORLY UNDERSTOOD WHETHER ELS AND SUBSEQUENT ADULT CHRONIC STRESS MODULATE EPIGENETIC MECHANISMS. WE EXAMINED THE EPIGENETIC MECHANISMS OF THE BDNF GENE IN THE HIPPOCAMPUS, WHICH MAY UNDERLIE STRESS VULNERABILITY TO POSTNATAL MATERNAL SEPARATION (MS) AND ADULT RESTRAINT STRESS (RS). RAT PUPS WERE SEPARATED FROM THEIR DAMS (3 H/DAY FROM P1-P21). WHEN THE PUPS REACHED ADULTHOOD (8 WEEKS OLD), WE INTRODUCED RS (2 H/DAY FOR 3 WEEKS) FOLLOWED BY ESCITALOPRAM TREATMENT. WE SHOWED THAT BOTH THE MS AND RS GROUPS EXPRESSED REDUCED LEVELS OF TOTAL AND EXON IV BDNF MRNA. FURTHERMORE, RS POTENTIATED MS-INDUCED DECREASES IN THESE EXPRESSION LEVELS. SIMILARLY, BOTH THE MS AND RS GROUPS SHOWED DECREASED LEVELS OF ACETYLATED HISTONE H3 AND H4 AT BDNF PROMOTER IV, AND RS EXACERBATED MS-INDUCED DECREASES OF H3 AND H4 ACETYLATION. BOTH THE MS AND RS GROUPS HAD INCREASED MECP2 LEVELS AT BDNF PROMOTER IV, AS WELL AS INCREASED HDAC5 MRNA, AND THE COMBINATION OF MS AND RS EXERTED A GREATER EFFECT ON THESE PARAMETERS THAN DID RS ALONE. IN THE FORCED SWIMMING TEST, THE IMMOBILITY TIME OF THE MS + RS GROUP WAS SIGNIFICANTLY HIGHER THAN THAT OF THE RS GROUP. ADDITIONALLY, CHRONIC ESCITALOPRAM TREATMENT RECOVERED THESE ALTERATIONS. OUR RESULTS SUGGEST THAT POSTNATAL MS AND SUBSEQUENT ADULT RS MODULATE EPIGENETIC CHANGES IN THE BDNF GENE, AND THAT THESE CHANGES MAY BE RELATED TO BEHAVIORAL PHENOTYPE. THESE EPIGENETIC MECHANISMS ARE INVOLVED IN ESCITALOPRAM ACTION.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
3   432  31 ANTIDEPRESSANT TREATMENT IS ASSOCIATED WITH EPIGENETIC ALTERATIONS IN THE PROMOTER OF P11 IN A GENETIC MODEL OF DEPRESSION. P11 (S100A10) HAS BEEN ASSOCIATED WITH THE PATHOPHYSIOLOGY OF DEPRESSION BOTH IN HUMAN AND RODENT MODELS. DIFFERENT TYPES OF ANTIDEPRESSANTS HAVE BEEN SHOWN TO INCREASE P11 LEVELS IN DISTINCT BRAIN REGIONS AND P11 GENE THERAPY WAS RECENTLY PROVEN EFFECTIVE IN REVERSING DEPRESSIVE-LIKE BEHAVIOURS IN MICE. HOWEVER, THE MOLECULAR MECHANISMS THAT GOVERN P11 GENE EXPRESSION IN RESPONSE TO ANTIDEPRESSANTS STILL REMAIN ELUSIVE. IN THIS STUDY WE REPORT DECREASED LEVELS OF P11, ASSOCIATED WITH HIGHER DNA METHYLATION IN THE PROMOTER REGION, IN THE PREFRONTAL CORTEX OF THE FLINDERS SENSITIVE LINE (FSL) GENETIC RODENT MODEL OF DEPRESSION. THIS HYPERMETHYLATED PATTERN WAS REVERSED TO NORMAL, AS INDICATED BY THE CONTROL LINE, AFTER CHRONIC ADMINISTRATION OF ESCITALOPRAM (A SELECTIVE SEROTONIN REUPTAKE INHIBITOR; SSRI). THE ESCITALOPRAM-INDUCED HYPOMETHYLATION WAS ASSOCIATED WITH BOTH AN INCREASE IN P11 GENE EXPRESSION AND A REDUCTION IN MRNA LEVELS OF TWO DNA METHYLTRANSFERASES THAT HAVE BEEN SHOWN TO MAINTAIN DNA METHYLATION IN ADULT FOREBRAIN NEURONS (DNMT1 AND DNMT3A). IN CONCLUSION, OUR DATA FURTHER SUPPORT A ROLE FOR P11 IN DEPRESSION-LIKE STATES AND SUGGEST THAT THIS GENE IS CONTROLLED BY EPIGENETIC MECHANISMS THAT CAN BE AFFECTED BY ANTIDEPRESSANT TREATMENT.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
4  1831  54 EFFECTS OF MATERNAL SEPARATION AND ANTIDEPRESSANT DRUG ON EPIGENETIC REGULATION OF THE BRAIN-DERIVED NEUROTROPHIC FACTOR EXON I PROMOTER IN THE ADULT RAT HIPPOCAMPUS. AIM: EARLY LIFE STRESS CAN INDUCE EPIGENETIC CHANGES THROUGH GENETIC AND ENVIRONMENTAL INTERACTIONS AND IS A RISK FACTOR FOR DEPRESSION. BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) HAS BEEN IMPLICATED IN THE PATHOPHYSIOLOGY OF DEPRESSION AND ANTIDEPRESSANT DRUG ACTION. WE INVESTIGATED EPIGENETIC CHANGES AT THE BDNF EXON I PROMOTER IN THE HIPPOCAMPUS OF ADULT RATS SUBJECTED TO MATERNAL SEPARATION (MS) DURING EARLY LIFE AND TREATED WITH AN ANTIDEPRESSANT DRUG AS ADULTS. METHODS: RAT PUPS WERE SUBJECTED TO MS FROM POSTNATAL DAY 1 TO 21 AND RECEIVED CHRONIC ESCITALOPRAM (ESC) AS ADULTS. WE ASSESSED THE EFFECTS OF MS AND ESC ON BDNF EXON I AND DNA METHYLTRANSFERASES (DNMT) MRNA LEVELS (QUANTITATIVE REVERSE-TRANSCRIPTION POLYMERASE CHAIN REACTION), ACETYLATED HISTONE H3, AND MECP2 BINDING TO THE BDNF PROMOTER I (CHROMATIN IMMUNOPRECIPITATION FOLLOWED BY REAL-TIME POLYMERASE CHAIN REACTION), AND BDNF PROTEIN LEVELS (ENZYME-LINKED IMMUNOSORBENT ASSAY). RESULTS: THE LEVELS OF BDNF PROTEIN, EXON I MRNA, HISTONE H3 ACETYLATION, AND DNMT1 AND DNMT3A MRNA WERE ALTERED IN THE MS GROUP COMPARED WITH THE CONTROL GROUP. SIGNIFICANT DECREASES WERE OBSERVED IN THE BDNF PROTEIN, EXON I MRNA, AND HISTONE H3 ACETYLATION LEVELS AND THERE WERE SIGNIFICANT INCREASES IN DNMT1 AND DNMT3A MRNA LEVELS. THE COMPARISON BETWEEN THE MS + ESC AND MS GROUPS REVEALED SIGNIFICANT INCREASES IN BDNF PROTEIN, EXON I MRNA, AND HISTONE H3 ACETYLATION LEVELS AND SIGNIFICANT DECREASES IN MECP2 AND DNMT1 AND DNMT3A MRNA LEVELS. CONCLUSION: THESE FINDINGS INDICATE THAT MS INDUCED EPIGENETIC CHANGES AT THE BDNF EXON I PROMOTER AND THESE CHANGES WERE PREVENTED BY ANTIDEPRESSANT DRUG TREATMENT DURING ADULTHOOD.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
5  1740  44 EARLY ENRICHED ENVIRONMENT PREVENTS EPIGENETIC P11 GENE CHANGES INDUCED BY ADULTHOOD STRESS IN MICE. POSITIVE EXPERIENCES IN EARLY LIFE MAY IMPROVE THE CAPACITY TO COPE WITH ADULTHOOD STRESS THROUGH EPIGENETIC MODIFICATION. WE INVESTIGATED WHETHER AN ENRICHED ENVIRONMENT (EE) IN THE POSTNATAL PERIOD AFFECTED EPIGENETIC CHANGES IN THE P11 GENE INDUCED BY CHRONIC UNPREDICTABLE STRESS (CUS) IN ADULT C57BL/6J MICE. EE WAS INTRODUCED FOR 5 WEEKS DURING POSTNATAL DAYS 21-55. AFTER EE, THE MICE WERE SUBJECTED TO CUS FOR 4 WEEKS. EE PREVENTED DEPRESSION-LIKE BEHAVIOR INDUCED BY ADULT CUS. EE PREVENTED A DECREASE IN P11 MRNA AND HISTONE H3 ACETYLATION INDUCED BY CUS, WITH CHANGES IN THE EXPRESSION OF HISTONE DEACETYLASE 5. MOREOVER, EE PREVENTED CHANGES IN TRIMETHYLATION OF HISTONE H3 LYSINE 4 (H3K4) AND H3K27 INDUCED BY CUS. FURTHERMORE, EE HAD POSITIVE EFFECTS ON BEHAVIOR AND EPIGENETIC ALTERATIONS IN ADULT MICE WITHOUT CUS. THESE RESULTS SUGGEST THAT ONE OF THE UNDERLYING MECHANISMS OF EARLY-LIFE EE MAY INVOLVE EPIGENETIC MODIFICATION OF THE HIPPOCAMPAL P11 GENE PROMOTER.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
6   718  26 CALCIUM-DEPENDENT INTRACELLULAR SIGNAL PATHWAYS IN PRIMARY CULTURED ADIPOCYTES AND ANK3 GENE VARIATION IN PATIENTS WITH BIPOLAR DISORDER AND HEALTHY CONTROLS. BIPOLAR DISORDER (BD) IS A CHRONIC PSYCHIATRIC DISORDER OF PUBLIC HEALTH IMPORTANCE AFFECTING >1% OF THE SWEDISH POPULATION. DESPITE PROGRESS, PATIENTS STILL SUFFER FROM CHRONIC MOOD SWITCHES WITH POTENTIAL SEVERE CONSEQUENCES. THUS, EARLY DETECTION, DIAGNOSIS AND INITIATION OF CORRECT TREATMENT ARE CRITICAL. CULTURED ADIPOCYTES FROM 35 PATIENTS WITH BD AND 38 HEALTHY CONTROLS WERE ANALYSED USING SIGNAL PATHWAY REPORTER ASSAYS, THAT IS, PROTEIN KINASE C (PKC), PROTEIN KINASE A (PKA), MITOGEN-ACTIVATED PROTEIN KINASES (EXTRACELLULAR SIGNAL-REGULATED KINASE (ERK) AND C-JUN N-TERMINAL KINASE (JNK)), MYC, WNT AND P53. THE LEVELS OF ACTIVATED TARGET TRANSCRIPTIONAL FACTORS WERE MEASURED IN ADIPOCYTES BEFORE AND AFTER STIMULATION WITH LITHIUM AND ESCITALOPRAM. VARIATIONS WERE ANALYSED IN THE LOCI OF 25 DIFFERENT SINGLE-NUCLEOTIDE POLYMORPHISMS (SNPS). ACTIVATION OF INTRACELLULAR SIGNALS IN SEVERAL PATHWAYS ANALYSED WERE SIGNIFICANTLY HIGHER IN PATIENTS THAN IN HEALTHY CONTROLS UPON DRUG STIMULATION, ESPECIALLY WITH ESCITALOPRAM STIMULATION OF PKC, JNK AND MYC, AS WELL AS LITHIUM-STIMULATED PKC, WHEREAS NO MEANINGFUL DIFFERENCE WAS OBSERVED BEFORE STIMULATION. UNIVARIATE ANALYSES OF CONTINGENCY TABLES FOR 80 CATEGORICAL SNP RESULTS VERSUS DIAGNOSES SHOWED A SIGNIFICANT LINK WITH THE ANK3 GENE (RS10761482; LIKELIHOOD RATIO CHI(2)=4.63; P=0.031). IN A MULTIVARIATE ORDINAL LOGISTIC FIT FOR DIAGNOSIS, A BACKWARD STEPWISE PROCEDURE SELECTED ANK3 AS THE REMAINING SIGNIFICANT PREDICTOR. COMPARISON OF THE ESCITALOPRAM-STIMULATED PKC ACTIVITY AND THE ANK3 GENOTYPE SHOWED THEM TO ADD THEIR SHARE OF THE DIAGNOSTIC VARIANCE, WITH NO INTERACTION (15% OF VARIANCE EXPLAINED, P<0.002). THE STUDY IS CROSS-SECTIONAL WITH NO LONGITUDINAL FOLLOW-UP. COHORTS ARE RELATIVELY SMALL WITH NO MEDICATION-FREE PATIENTS, AND THERE ARE NO 'ILL PATIENT' CONTROLS. IT TAKES 3 TO 4 WEEKS OF CULTURE TO EXPAND ADIPOCYTES THAT MAY CHANGE EPIGENETIC PROFILES BUT REMOVE THE POSSIBILITY OF MEDICATION EFFECTS. ABNORMALITIES IN THE REACTIVITY OF INTRACELLULAR SIGNAL PATHWAYS TO STIMULATION AND THE ANK3 GENOTYPE MAY BE ASSOCIATED WITH PATHOGENESIS OF BD. ALGORITHMS USING BIOLOGICAL PATTERNS SUCH AS PATHWAY REACTIVITY TOGETHER WITH STRUCTURAL GENETIC SNP DATA MAY PROVIDE OPPORTUNITIES FOR EARLIER DETECTION AND EFFECTIVE TREATMENT OF BD.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
7  4397  40 MODULATION OF DNA METHYLATION AND GENE EXPRESSION IN RODENT CORTICAL NEUROPLASTICITY PATHWAYS EXERTS RAPID ANTIDEPRESSANT-LIKE EFFECTS. BACKGROUND: STRESS INCREASES DNA METHYLATION, PRIMARILY A SUPPRESSIVE EPIGENETIC MECHANISM CATALYZED BY DNA METHYLTRANSFERASES (DNMT), AND DECREASES THE EXPRESSION OF GENES INVOLVED IN NEURONAL PLASTICITY AND MOOD REGULATION. DESPITE CHRONIC ANTIDEPRESSANT TREATMENT DECREASES STRESS-INDUCED DNA METHYLATION, IT IS NOT KNOWN WHETHER INHIBITION OF DNMT WOULD CONVEY RAPID ANTIDEPRESSANT-LIKE EFFECTS. AIM: THIS WORK TESTED SUCH A HYPOTHESIS AND EVALUATED WHETHER A BEHAVIORAL EFFECT INDUCED BY DNMT INHIBITORS (DNMTI) CORRESPONDS WITH CHANGES IN DNA METHYLATION AND TRANSCRIPT LEVELS IN GENES CONSISTENTLY ASSOCIATED WITH THE NEUROBIOLOGY OF DEPRESSION AND SYNAPTIC PLASTICITY (BDNF, TRKB, 5-HT(1A), NMDA, AND AMPA). METHODS: MALE WISTAR RATS RECEIVED INTRAPERITONEAL (I.P.) INJECTION OF TWO PHARMACOLOGICALLY DIFFERENT DNMTI (5-AZAD 0.2 AND 0.6 MG/KG OR RG108 0.6 MG/KG) OR VEHICLE (1 ML/KG), 1 H OR 7 DAYS BEFORE THE LEARNED HELPLESSNESS TEST (LH). DNA METHYLATION IN TARGET GENES AND THE CORRESPONDENT TRANSCRIPT LEVELS WERE MEASURED IN THE HIPPOCAMPUS (HPC) AND PREFRONTAL CORTEX (PFC) USING MEDIP-QPCR. IN PARALLEL SEPARATE GROUPS, THE ANTIDEPRESSANT-LIKE EFFECT OF 5-AZAD AND RG108 WAS INVESTIGATED IN THE FORCED SWIMMING TEST (FST). THE INVOLVEMENT OF CORTICAL BDNF-TRKB-MTOR PATHWAYS WAS ASSESSED BY INTRA-VENTRAL MEDIAL PFC (VMPFC) INJECTIONS OF RAPAMYCIN (MTOR INHIBITOR), K252A (TRKB RECEPTOR ANTAGONIST), OR VEHICLE (0.2 MUL/SIDE). RESULTS: WE FOUND THAT BOTH 5-AZAD AND RG108 ACUTELY AND 7 DAYS BEFORE THE TEST DECREASED ESCAPE FAILURES IN THE LH. LH STRESS INCREASED DNA METHYLATION AND DECREASED TRANSCRIPT LEVELS OF BDNF IV AND TRKB IN THE PFC, EFFECTS THAT WERE NOT SIGNIFICANTLY ATTENUATED BY RG108 TREATMENT. THE SYSTEMIC ADMINISTRATION OF 5-AZAD (0.2 MG/KG) AND RG108 (0.2 MG/KG) INDUCED AN ANTIDEPRESSANT-LIKE EFFECT IN FST, WHICH WAS, HOWEVER, ATTENUATED BY TRKB AND MTOR INHIBITION INTO THE VMPFC. CONCLUSION: THESE FINDINGS SUGGEST THAT ACUTE INHIBITION OF STRESS-INDUCED DNA METHYLATION PROMOTES RAPID AND SUSTAINED ANTIDEPRESSANT EFFECTS ASSOCIATED WITH INCREASED BDNF-TRKB-MTOR SIGNALING IN THE PFC.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
8  5651  37 SEX DIFFERENCES IN THE EPIGENETIC REGULATION OF CHRONIC VISCERAL PAIN FOLLOWING UNPREDICTABLE EARLY LIFE STRESS. BACKGROUND: WE PREVIOUSLY REPORTED THAT EARLY LIFE STRESS (ELS) DYSREGULATED GLUCOCORTICOID RECEPTOR (GR) AND CORTICOTROPHIN-RELEASING HORMONE (CRH) EXPRESSION IN THE CENTRAL NUCLEUS OF THE AMYGDALA (CEA). EPIGENETIC MODIFICATIONS SERVE AS MEMORIES OF ADVERSE EVENTS THAT OCCURRED DURING EARLY LIFE. THEREFORE, WE HYPOTHESIZED THAT EPIGENETIC MECHANISMS ALTER GR AND CRH EXPRESSION IN THE CEA AND UNDERLIE CHRONIC VISCERAL PAIN AFTER ELS. METHODS: NEONATAL RATS WERE EXPOSED TO UNPREDICTABLE, PREDICTABLE ELS, OR ODOR ONLY (NO STRESS CONTROL) FROM POSTNATAL DAYS 8 TO 12. IN ADULTHOOD, VISCERAL SENSITIVITY WAS ASSESSED OR THE CEA WAS ISOLATED FOR WESTERN BLOT OR CHIP-QPCR TO STUDY HISTONE MODIFICATIONS AT THE GR AND CRH PROMOTERS. FEMALE ADULT RATS UNDERWENT STEREOTAXIC IMPLANTATION OF INDWELLING CANNULAS FOR MICROINJECTIONS OF GARCINOL (HAT INHIBITOR) INTO THE CEA. AFTER 7 DAYS OF MICROINJECTIONS, VISCERAL SENSITIVITY WAS ASSESSED OR THE CEA WAS ISOLATED FOR CHIP-QPCR ASSAYS. RESULTS: UNPREDICTABLE ELS INCREASED VISCERAL SENSITIVITY IN ADULT FEMALE RATS, BUT NOT IN MALE COUNTERPARTS. ELS INCREASED HISTONE 3 LYSINE 9 (H3K9) ACETYLATION IN THE CEA AND H3K9 ACETYLATION LEVELS AT THE GR PROMOTER IN THE CEA OF ADULT FEMALE RATS. AFTER UNPREDICTABLE ELS, H3K9 ACETYLATION WAS INCREASED AND GR BINDING WAS DECREASED AT THE CRH PROMOTER. ADMINISTRATION OF GARCINOL IN THE CEA OF ADULT FEMALES, THAT UNDERWENT UNPREDICTABLE ELS, NORMALIZED H3K9 ACETYLATION AND RESTORED GR BINDING AT THE CRH PROMOTER. CONCLUSION: DYSREGULATED HISTONE ACETYLATION AND GR BINDING AT THE CRH PROMOTER IN THE CEA ARE AN IMPORTANT MECHANISM FOR "MEMORIZING" ELS EVENTS MEDIATING VISCERAL PAIN IN ADULTHOOD.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
9  1809  40 EFFECTS OF ANTIPSYCHOTIC DRUGS ON THE EPIGENETIC MODIFICATION OF BRAIN-DERIVED NEUROTROPHIC FACTOR GENE EXPRESSION IN THE HIPPOCAMPI OF CHRONIC RESTRAINT STRESS RATS. RECENT STUDIES HAVE SHOWN THAT ANTIPSYCHOTIC DRUGS HAVE EPIGENETIC EFFECTS. HOWEVER, THE EFFECTS OF ANTIPSYCHOTIC DRUGS ON HISTONE MODIFICATION REMAIN UNCLEAR. THEREFORE, WE INVESTIGATED THE EFFECTS OF ANTIPSYCHOTIC DRUGS ON THE EPIGENETIC MODIFICATION OF THE BDNF GENE IN THE RAT HIPPOCAMPUS. RATS WERE SUBJECTED TO CHRONIC RESTRAINT STRESS (6 H/D FOR 21 D) AND THEN WERE ADMINISTERED WITH EITHER OLANZAPINE (2 MG/KG) OR HALOPERIDOL (1 MG/KG). THE LEVELS OF HISTONE H3 ACETYLATION AND MECP2 BINDING AT BDNF PROMOTER IV WERE ASSESSED WITH CHROMATIN IMMUNOPRECIPITATION ASSAYS. THE MRNA LEVELS OF TOTAL BDNF WITH EXON IV, HDAC5, DNMT1, AND DNMT3A WERE ASSESSED WITH A QUANTITATIVE RT-PCR PROCEDURE. CHRONIC RESTRAINT STRESS RESULTED IN THE DOWNREGULATION OF TOTAL AND EXON IV BDNF MRNA LEVELS AND A DECREASE IN HISTONE H3 ACETYLATION AND AN INCREASE IN MECP2 BINDING AT BDNF PROMOTER IV. FURTHERMORE, THERE WERE ROBUST INCREASES IN THE EXPRESSION OF HDAC5 AND DNMTS. OLANZAPINE ADMINISTRATION LARGELY PREVENTED THESE CHANGES. THE ADMINISTRATION OF HALOPERIDOL HAD NO EFFECT. THESE FINDINGS SUGGEST THAT THE ANTIPSYCHOTIC DRUG OLANZAPINE INDUCED HISTONE MODIFICATION OF BDNF GENE EXPRESSION IN THE HIPPOCAMPUS AND THAT THESE EPIGENETIC ALTERATIONS MAY REPRESENT ONE OF THE MECHANISMS UNDERLYING THE ACTIONS OF ANTIPSYCHOTIC DRUGS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
10  3177  38 H3K9ME2 REGULATION OF BDNF EXPRESSION IN THE HIPPOCAMPUS AND MEDIAL PREFRONTAL CORTEX IS INVOLVED IN THE DEPRESSIVE-LIKE PHENOTYPE INDUCED BY MATERNAL SEPARATION IN MALE RATS. BACKGROUND: EARLY LIFE STRESS (ELS) INDUCES A DEPRESSIVE-LIKE PHENOTYPE AND INCREASES THE RISK OF DEPRESSION. BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) HAS BEEN CONFIRMED TO BE INVOLVED IN THE PATHOPHYSIOLOGY OF DEPRESSION. HOWEVER, THE MECHANISM BY WHICH ELS ALTERS THE EPIGENETIC REGULATION OF BDNF AND CHANGES SUSCEPTIBILITY TO DEPRESSION HAS NOT BEEN FULLY CLARIFIED. METHODS: THE PRESENT STUDY USED MATERNAL SEPARATION (MS) AND CHRONIC UNPREDICTED MILD STRESS (CUMS) TO ESTABLISH AN MS ANIMAL MODEL AND A DEPRESSIVE ANIMAL MODEL. WE ASSESSED DEPRESSIVE-LIKE BEHAVIOURS, INCLUDING ANHEDONIA, LOCOMOTOR ACTIVITY, ANXIETY-LIKE BEHAVIOUR, AND SPATIAL MEMORY, USING THE SUCROSE PREFERENCE TEST, THE OPEN FIELD TEST, THE ELEVATED PLUS MAZE TEST, AND THE MORRIS WATER MAZE TEST. WE ALSO INVESTIGATED BDNF AND H3K9ME2 EXPRESSION IN THE HIPPOCAMPUS AND MEDIAL PREFRONTAL CORTEX (MPFC) BY IMMUNOHISTOCHEMISTRY, WESTERN BLOTTING, AND QPCR ANALYSIS. ADDITIONALLY, WE USED UNC0642, A SMALL MOLECULE INHIBITOR OF HISTONE METHYLTRANSFERASE (G9A), AS AN INTERVENTION. RESULTS: THE RESULTS SHOWED THAT CUMS INDUCED DEPRESSIVE-LIKE BEHAVIOURS IN RATS AND RESULTED IN INCREASED H3K9ME2 EXPRESSION AND DECREASED BDNF EXPRESSION IN THE HIPPOCAMPUS AND MPFC. MORE IMPORTANTLY, ADULT MS RATS EXPERIENCING CUMS HAD MORE SEVERE DEPRESSIVE BEHAVIOURS, HAD HIGHER EXPRESSION OF H3K9ME2 IN THE HIPPOCAMPUS AND MPFC, AND HAD LOWER EXPRESSION OF BDNF IN THE HIPPOCAMPUS AND MPFC. IN ADDITION, ADMINISTRATION OF THE G9A INHIBITOR REVERSED MOST OF THE CHANGES. CONCLUSIONS: OUR STUDY SUGGESTS THAT ELS CHANGED BDNF AND H3K9ME2 EXPRESSION IN THE RAT BRAIN, RESULTING IN A DEPRESSIVE-LIKE PHENOTYPE.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
11   434  30 ANTIDEPRESSANT-LIKE EFFECT OF SODIUM BUTYRATE IS ASSOCIATED WITH AN INCREASE IN TET1 AND IN 5-HYDROXYMETHYLATION LEVELS IN THE BDNF GENE. BACKGROUND: EPIGENETIC DRUGS LIKE SODIUM BUTYRATE (NAB) SHOW ANTIDEPRESSANT-LIKE EFFECTS IN PRECLINICAL STUDIES, BUT THE EXACT MOLECULAR MECHANISMS OF THE ANTIDEPRESSANT EFFECTS REMAIN UNKNOWN. WHILE RESEARCH USING NAB HAS MAINLY FOCUSED ON ITS ROLE AS A HISTONE DEACETYLASE INHIBITOR (HDACI), THERE IS ALSO EVIDENCE THAT NAB AFFECTS DNA METHYLATION. METHODS: THE PURPOSE OF THIS STUDY WAS TO EXAMINE NAB'S PUTATIVE ANTIDEPRESSANT-LIKE EFFICACY IN RELATION TO DNA METHYLATION CHANGES IN THE PREFRONTAL CORTEX OF AN ESTABLISHED GENETIC RAT MODEL OF DEPRESSION (THE FLINDERS SENSITIVE LINE [FSL]) AND ITS CONTROLS (THE FLINDERS RESISTANT LINE). RESULTS: THE FSL RATS HAD LOWER LEVELS OF TEN-ELEVEN TRANSLOCATION METHYLCYTOSINE DIOXYGENASE 1 (TET1), WHICH CATALYZES THE CONVERSION OF DNA METHYLATION TO HYDROXYMETHYLATION. AS INDICATED BY THE BEHAVIORAL DESPAIR TEST, CHRONIC ADMINISTRATION OF NAB HAD ANTIDEPRESSANT-LIKE EFFECTS IN THE FSL AND WAS ACCOMPANIED BY INCREASED LEVELS OF TET1. THE TET1 UPREGULATION WAS ALSO ASSOCIATED WITH AN INCREASE OF HYDROXYMETHYLATION AND A DECREASE OF METHYLATION IN BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF), A GENE ASSOCIATED WITH NEUROGENESIS AND SYNAPTIC PLASTICITY. THESE EPIGENETIC CHANGES WERE ASSOCIATED WITH A CORRESPONDING BDNF OVEREXPRESSION. CONCLUSIONS: OUR DATA SUPPORT THE ANTIDEPRESSANT EFFICACY OF HDACIS AND SUGGEST THAT THEIR EPIGENETIC EFFECTS MAY ALSO INCLUDE DNA METHYLATION CHANGES THAT ARE MEDIATED BY DEMETHYLATION-FACILITATING ENZYMES LIKE TET1.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
12   513  24 ASSOCIATION OF SEROTONIN TRANSPORTER GENE ALUJB METHYLATION WITH MAJOR DEPRESSION, AMYGDALA RESPONSIVENESS, 5-HTTLPR/RS25531 POLYMORPHISM, AND STRESS. DNA METHYLATION PROFILES OF THE SEROTONIN TRANSPORTER GENE (SLC6A4) HAVE BEEN SHOWN TO ALTER SLC6A4 EXPRESSION, DRIVE ANTIDEPRESSANT TREATMENT RESPONSE AND MODIFY BRAIN FUNCTIONS. THIS STUDY INVESTIGATED WHETHER METHYLATION OF AN ALUJB ELEMENT IN THE SLC6A4 PROMOTOR WAS ASSOCIATED WITH MAJOR DEPRESSIVE DISORDER (MDD), AMYGDALA REACTIVITY TO EMOTIONAL FACES, 5-HTTLPR/RS25531 POLYMORPHISM, AND RECENT STRESS. MDD PATIENTS (N=122) AND HEALTHY CONTROLS (HC, N=176) UNDERWENT FMRI DURING AN EMOTIONAL FACE-MATCHING TASK. INDIVIDUAL SLC6A4 ALUJB METHYLATION PROFILES WERE ASCERTAINED AND ASSOCIATED WITH MDD, AMYGDALA REACTIVITY, 5-HTTLPR/RS25531, AND STRESS. SLC6A4 ALUJB METHYLATION WAS SIGNIFICANTLY LOWER IN MDD COMPARED TO HC AND IN STRESSED COMPARED TO LESS STRESSED PARTICIPANTS. LOWER ALUJB METHYLATION WAS PARTICULARLY FOUND IN 5-HTTLPR/RS25531 RISK ALLELE CARRIERS UNDER STRESS AND CORRELATED WITH LESS DEPRESSIVE EPISODES. FMRI ANALYSIS REVEALED A SIGNIFICANT INTERACTION OF ALUJB METHYLATION AND DIAGNOSIS IN THE AMYGDALA, WITH MDD PATIENTS SHOWING LOWER ALUJB METHYLATION ASSOCIATED WITH DECREASED AMYGDALA REACTIVITY. WHILE NO JOINT EFFECT OF ALUJB METHYLATION AND 5-HTTLPR/RS25531 EXISTED, RISK ALLELE CARRIERS SHOWED SIGNIFICANTLY INCREASED BILATERAL AMYGDALA ACTIVATION. THESE FINDINGS SUGGEST A ROLE OF SLC6A4 ALUJB METHYLATION IN MDD, AMYGDALA REACTIVITY, AND STRESS REACTION, PARTLY INTERWOVEN WITH 5-HTTLPR/RS25531 EFFECTS. PATIENTS WITH LOW METHYLATION IN CONJUNCTION WITH A SHORTER MDD HISTORY AND DECREASED AMYGDALA REACTIVITY MIGHT FEATURE A MORE STRESS-ADAPTIVE EPIGENETIC PROCESS, MAYBE VIA THEORETICALLY POSSIBLE ENDOGENOUS ANTIDEPRESSANT-LIKE EFFECTS. IN CONTRAST, PATIENTS WITH HIGHER METHYLATION MIGHT POSSIBLY SUFFER FROM IMPAIRED EPIGENETIC ADAPTION TO CHRONIC STRESS. FURTHER, THE 5-HTTLPR/RS25531 ASSOCIATION WITH AMYGDALA ACTIVATION WAS CONFIRMED IN OUR LARGE SAMPLE.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
13  5191  40 PRENATAL DEXAMETHASONE EXPOSURE PROGRAMS THE DECREASED TESTOSTERONE SYNTHESIS IN OFFSPRING RATS BY LOW LEVEL OF ENDOGENOUS GLUCOCORTICOIDS. PRENATAL DEXAMETHASONE EXPOSURE (PDE) CAN DECREASE MATERNAL ENDOGENOUS GLUCOCORTICOID LEVEL AND INDUCE TESTICULAR DYSPLASIA IN MALE OFFSPRING RATS. IN THIS STUDY WE INVESTIGATED LOW LEVEL ENDOGENOUS GLUCOCORTICOID-MEDIATED TESTICULAR DYSPLASIA IN PDE OFFSPRING AND ELUCIDATED THE INTRAUTERINE EPIGENETIC PROGRAMMING MECHANISMS. PREGNANT RATS WERE INJECTED WITH DEXAMETHASONE (0.2 MG.KG(-1).D(-1), SC) ON GESTATIONAL DAY (GD) 9-20. THE OFFSPRING RAT BLOOD AND TESTIS WERE COLLECTED AFTER EUTHANASIA ON GD20, POSTNATAL WEEK (PW) 12 OR PW28. WE SHOWED THAT PDE INDUCED ABNORMAL MORPHOLOGY OF TESTIS AND SIGNIFICANTLY DECREASED THE EXPRESSION OF TESTOSTERONE SYNTHESIS-RELATED GENES AS WELL AS TESTOSTERONE PRODUCTION BEFORE AND AFTER BIRTH. MEANWHILE, SERUM CORTICOSTERONE, THE EXPRESSION AND HISTONE 3 LYSINE 14 ACETYLATION (H3K14AC) OF TESTICULAR INSULIN-LIKE GROWTH FACTOR 1 (IGF1) WERE SIGNIFICANTLY DECREASED. AFTER THE PREGNANT RATS WERE SUBJECTED TO CHRONIC STRESS FOR 2 WEEKS (PW10-12), SERUM CORTICOSTERONE LEVEL WAS INCREASED IN THE ADULT PDE OFFSPRING, AND THE ABOVE-MENTIONED OTHER INDICATORS WERE ALSO IMPROVED. CULTURED LEYDIG CELLS (TM3) WERE TREATED WITH CORTICOSTERONE (62.5-500 NM) IN VITRO. WE SHOWED THAT CORTICOSTERONE CONCENTRATION-DEPENDENTLY INHIBITED GLUCOCORTICOID RECEPTOR ALPHA (GRALPHA) AND MIR-124-3P EXPRESSION, INCREASED HISTONE DEACETYLASE 5 (HDAC5) EXPRESSION, AND DECREASED IGF1 H3K14AC LEVEL AND THE EXPRESSION OF IGF1/STEROIDOGENIC ACUTE REGULATORY PROTEIN (STAR), SUGGESTING THAT CORTICOSTERONE AT LOWER THAN PHYSIOLOGICAL LEVEL (<500 NM) INHIBITED TESTOSTERONE SYNTHESIS BY REDUCING H3K14AC AND THE EXPRESSION LEVEL OF IGF1 THROUGH GRALPHA/MIR-124-3P/HDAC5 PATHWAY. IN CONCLUSION, PDE CAN CAUSE PERSISTENT INHIBITION OF TESTOSTERONE SYNTHESIS BEFORE AND AFTER BIRTH IN THE OFFSPRING RATS BY LOW LEVEL OF ENDOGENOUS GLUCOCORTICOIDS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
14  6108  41 THE ENRICHED ENVIRONMENT AMELIORATES CHRONIC UNPREDICTABLE MILD STRESS-INDUCED DEPRESSIVE-LIKE BEHAVIORS AND COGNITIVE IMPAIRMENT BY ACTIVATING THE SIRT1/MIR-134 SIGNALING PATHWAY IN HIPPOCAMPUS. BACKGROUND: CHRONIC UNPREDICTABLE MILD STRESS (CUMS) IS AN IMPORTANT RISK FACTOR FOR DEPRESSION AND COGNITIVE DEFICITS IN HUMANS. ENRICHED ENVIRONMENT (EE) SHOWED A BENEFICIAL EFFECT ON DEPRESSION AND COGNITION BY ENHANCING BRAIN DERIVED NEUROTROPHIC FACTOR (BDNF) EXPRESSION AND SYNAPTIC PLASTICITY. HOWEVER, IT IS STILL NOT CLEARLY UNDERSTOOD WHETHER AN EPIGENETIC MECHANISM IS INVOLVED IN THE BDNF MODULATION AND SYNAPTIC PLASTICITY THAT OCCURS AFTER EE TREATMENT FOR THE DEPRESSIVE-LIKE BEHAVIORS AND COGNITIVE DEFICITS ELICITED BY CUMS. IN THIS STUDY, WE INVESTIGATED THE POSSIBLE MECHANISM OF THE NEUROPROTECTIVE EFFECT OF EE. METHODS: ALL RATS WERE EXPOSED TO THE 5-WEEK CUMS PROCEDURE EXCEPT THE CONTROL GROUP. AFTER CUMS PROCEDURE, SOME RATS WERE STEREOTAXICALLY INJECTED WITH SIRT1 PHARMACOLOGIC INHIBITOR EX527 OR SIRT1 KNOCKING DOWN LENTIVIRUS (SH-SIRT1) IN THE HIPPOCAMPUS FOLLOWED BY EE TREATMENT FOR 3 WEEKS. OTHER RATS WERE DIRECTLY SUBJECTED TO EE TREATMENT WITHOUT STEREOTAXIC INJECTION. BEHAVIORAL TESTS WERE USED TO APPRAISE DEPRESSION AND COGNITION AFTER EE TREATMENT. THEN EPIGENETIC MOLECULES, SYNAPTIC PROTEINS, DENDRITIC SPINE DENSITY AND BRANCHES, AND SYNAPTIC MORPHOLOGY OF THE DORSAL HIPPOCAMPUS WERE DETERMINED. RESULTS: WE FOUND THAT CUMS INDUCED DEPRESSIVE-LIKE BEHAVIORS INCLUDING DECREASED SUCROSE PREFERENCE RATIO, PROLONGED IMMOBILITY AND REDUCED LOCOMOTOR AND EXPLORATORY ACTIVITY; COGNITIVE DEFICITS INCLUDING SPATIAL LEARNING AND MEMORY IMPAIRMENT; REDUCED DENDRITIC SPINE DENSITY AND NUMBER OF BRANCHES; THINNED POSTSYNAPTIC DENSITY; DOWNREGULATED SIRT1/MICRORNA-134 PATHWAY, DECREASED BDNF AND SYNAPTIC PROTEINS INCLUDING SYNAPTOPHYSIN (SYN) AND POSTSYNAPTIC DENSITY PROTEIN 95 (PSD95) EXPRESSION IN THE HIPPOCAMPUS. HOWEVER, THE CUMS-INDUCED DEPRESSIVE-LIKE BEHAVIORS, COGNITIVE DEFICITS, DENDRITIC SPINE DENSITY AND BRANCH NUMBER REDUCTION, POSTSYNAPTIC DENSITY THINNING, SIRT1/MICRORNA-134 PATHWAY DOWNREGULATION, BDNF AND SYNAPTIC PROTEINS REDUCTION, INCLUDING SYNAPTOPHYSIN (SYN) AND POSTSYNAPTIC DENSITY PROTEIN 95 (PSD95), WERE REVERSED BY EE TREATMENT. HOWEVER, DEPRESSIVE-LIKE BEHAVIORS AND COGNITIVE DEFICITS WERE OBSERVED AGAIN IN RATS SUBJECTED TO STEREOTAXIC INJECTION WITH EX527 OR SH-SIRT1. FURTHERMORE, THIS STUDY ALSO FOUND THAT SIRT1/MICRORNA-134 REGULATES THE DOWNSTREAM MOLECULES BDNF, AND THE SYNAPTIC PROTEINS SYN AND PSD95 IN PRIMARY CULTURED HIPPOCAMPAL NEURONS. CONCLUSIONS: THIS STUDY PROVIDES EVIDENCE FOR THE NEUROPROTECTIVE ROLE OF EE ON DEPRESSION AND COGNITIVE DEFICITS BY ACTIVATING THE SIRT1/MICRORNA-134 PATHWAY, WHICH ACCOUNTS FOR THE REGULATION OF SYNAPTIC PROTEINS, INCLUDING BDNF, PSD95 AND SYN, DENDRITIC REMODELING AND ULTRASTRUCTURE CHANGES OF SYNAPSES IN THE HIPPOCAMPUS.	2019	

15  2187  53 EPIGENETIC MECHANISMS UNDERLYING STRESS-INDUCED VISCERAL PAIN: RESILIENCE VERSUS VULNERABILITY IN A TWO-HIT MODEL OF EARLY LIFE STRESS AND CHRONIC ADULT STRESS. BACKGROUND: WOMEN WITH A HISTORY OF EARLY LIFE STRESS (ELS) HAVE A HIGHER RISK OF DEVELOPING IRRITABLE BOWEL SYNDROME (IBS). IN ADDITION, CHRONIC STRESS IN ADULTHOOD CAN EXACERBATE IBS SYMPTOMS SUCH AS ABDOMINAL PAIN DUE TO VISCERAL HYPERSENSITIVITY. WE PREVIOUSLY SHOWED THAT SEX AND THE PREDICTABILITY OF ELS DETERMINE WHETHER RATS DEVELOP VISCERAL HYPERSENSITIVITY IN ADULTHOOD. IN FEMALE RATS, UNPREDICTABLE ELS CONFERS VULNERABILITY AND RESULTS IN VISCERAL HYPERSENSITIVITY, WHEREAS PREDICTABLE ELS INDUCES RESILIENCE AND DOES NOT INDUCE VISCERAL HYPERSENSITIVITY IN ADULTHOOD. HOWEVER, THIS RESILIENCE IS LOST AFTER EXPOSURE TO CHRONIC STRESS IN ADULTHOOD LEADING TO AN EXACERBATION OF VISCERAL HYPERSENSITIVITY. EVIDENCE SUGGESTS THAT CHANGES IN HISTONE ACETYLATION AT THE PROMOTER REGIONS OF GLUCOCORTICOID RECEPTOR (GR) AND CORTICOTROPHIN-RELEASING FACTOR (CRF) IN THE CENTRAL NUCLEUS OF THE AMYGDALA (CEA) UNDERLIE STRESS-INDUCED VISCERAL HYPERSENSITIVITY. HERE, WE AIMED TO INVESTIGATE THE ROLE OF HISTONE ACETYLATION IN THE CEA ON VISCERAL HYPERSENSITIVITY IN A TWO-HIT MODEL OF ELS FOLLOWED BY CHRONIC STRESS IN ADULTHOOD. METHODS: MALE AND FEMALE NEONATAL RATS WERE EXPOSED TO UNPREDICTABLE, PREDICTABLE ELS, OR ODOR ONLY (NO STRESS CONTROL) FROM POSTNATAL DAYS 8 TO 12. IN ADULTHOOD, RATS UNDERWENT STEREOTAXIC IMPLANTATION OF INDWELLING CANNULAS. RATS WERE EXPOSED TO CHRONIC WATER AVOIDANCE STRESS (WAS, 1 H/DAY FOR 7 DAYS) OR SHAM STRESS AND RECEIVED INFUSIONS OF VEHICLE, THE HISTONE DEACETYLASE INHIBITOR TRICHOSTATIN A (TSA) OR THE HISTONE ACETYLTRANSFERASE INHIBITOR GARCINOL (GAR) AFTER EACH WAS SESSION. 24 H AFTER THE FINAL INFUSION, VISCERAL SENSITIVITY WAS ASSESSED AND THE CEA WAS REMOVED FOR MOLECULAR EXPERIMENTS. RESULTS: IN THE TWO-HIT MODEL (ELS + WAS), FEMALE RATS PREVIOUSLY EXPOSED TO PREDICTABLE ELS, SHOWED A SIGNIFICANT REDUCTION IN HISTONE 3 LYSINE 9 (H3K9) ACETYLATION AT THE GR PROMOTER AND A SIGNIFICANT INCREASE IN H3K9 ACETYLATION AT THE CRF PROMOTER. THESE EPIGENETIC CHANGES WERE ASSOCIATED WITH CHANGES IN GR AND CRF MRNA EXPRESSION IN THE CEA AND AN EXACERBATION OF STRESS-INDUCED VISCERAL HYPERSENSITIVITY IN FEMALE ANIMALS. TSA INFUSIONS IN THE CEA ATTENUATED THE EXACERBATED STRESS-INDUCED VISCERAL HYPERSENSITIVITY, WHEREAS GAR INFUSIONS ONLY PARTIALLY AMELIORATED ELS+WAS INDUCED VISCERAL HYPERSENSITIVITY. CONCLUSION: THE TWO-HIT MODEL OF ELS FOLLOWED BY WAS IN ADULTHOOD REVEALED THAT EPIGENETIC DYSREGULATION OCCURS AFTER EXPOSURE TO STRESS IN TWO IMPORTANT PERIODS OF LIFE AND CONTRIBUTES TO THE DEVELOPMENT OF VISCERAL HYPERSENSITIVITY. THESE ABERRANT UNDERLYING EPIGENETIC CHANGES MAY EXPLAIN THE EXACERBATION OF STRESS-INDUCED ABDOMINAL PAIN IN IBS PATIENTS.	2023	
                                                                     
16   219  34 ACUTE IMMOBILIZATION STRESS FOLLOWING CONTEXTUAL FEAR CONDITIONING REDUCES FEAR MEMORY: TIMING IS ESSENTIAL. BACKGROUND: HISTONE ACETYLATION IS REGULATED IN RESPONSE TO STRESS AND PLAYS AN IMPORTANT ROLE IN LEARNING AND MEMORY. CHRONIC STRESS IS KNOWN TO DETERIORATE COGNITION, WHEREAS ACUTE STRESS FACILITATES MEMORY FORMATION. HOWEVER, WHETHER ACUTE STRESS FACILITATES MEMORY FORMATION WHEN IT IS APPLIED AFTER FEAR STIMULATION IS NOT YET KNOWN. THEREFORE, THIS STUDY AIMED TO INVESTIGATE THE EFFECT OF ACUTE STRESS APPLIED AFTER FEAR TRAINING ON MEMORY FORMATION, MRNA EXPRESSION OF BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF), EPIGENETIC REGULATION OF BDNF EXPRESSION, AND CORTICOSTERONE LEVEL IN MICE IN VIVO. METHODS: MICE WERE SUBJECTED TO ACUTE IMMOBILIZATION STRESS FOR 30 MIN AT 60 OR 90 MIN AFTER CONTEXTUAL FEAR CONDITIONING TRAINING, AND ACETYLATION OF HISTONE 3 AT LYSINE 14 (H3K14) AND LEVEL OF CORTICOSTERONE WERE MEASURED USING WESTERN BLOT ANALYSIS AND ENZYME-LINKED IMMUNOSORBENT ASSAY (ELISA), RESPECTIVELY. A FREEZING BEHAVIOR TEST WAS PERFORMED 24 H AFTER TRAINING, AND MRNA EXPRESSION OF BDNF WAS MEASURED USING REAL-TIME POLYMERASE CHAIN REACTIONS. DIFFERENT GROUPS OF MICE WERE USED FOR EACH TEST. RESULTS: FREEZING BEHAVIOR SIGNIFICANTLY DECREASED WITH THE DOWN-REGULATION OF BDNF MRNA EXPRESSION CAUSED BY ACUTE IMMOBILIZATION STRESS AT 60 MIN AFTER FEAR CONDITIONING TRAINING OWING TO THE REDUCTION OF H3K14 ACETYLATION. HOWEVER, BDNF MRNA EXPRESSION AND H3K14 ACETYLATION WERE NOT REDUCED IN ANIMALS SUBJECTED TO IMMOBILIZATION STRESS AT 90 MIN AFTER THE TRAINING. FURTHER, THE CORTICOSTERONE LEVEL WAS SIGNIFICANTLY HIGH IN MICE SUBJECTED TO IMMOBILIZATION STRESS AT 60 MIN AFTER THE TRAINING. CONCLUSION: ACUTE IMMOBILIZATION STRESS FOR 30 MIN AT 60 MIN AFTER FEAR CONDITIONING TRAINING IMPAIRED MEMORY FORMATION AND REDUCED BDNF MRNA EXPRESSION AND H3K14 ACETYLATION IN THE HIPPOCAMPUS OF MICE OWING TO THE HIGH LEVEL OF CORTICOSTERONE.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
17  1320  28 DEMETHYLATION REGULATION OF BDNF GENE EXPRESSION IN DORSAL ROOT GANGLION NEURONS IS IMPLICATED IN OPIOID-INDUCED PAIN HYPERSENSITIVITY IN RATS. REPEATED ADMINISTRATION OF MORPHINE MAY RESULT IN OPIOID-INDUCED HYPERSENSITIVITY (OIH), WHICH INVOLVES ALTERED EXPRESSION OF NUMEROUS GENES, INCLUDING BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) IN DORSAL ROOT GANGLION (DRG) NEURONS. YET, IT REMAINS UNCLEAR HOW BDNF EXPRESSION IS INCREASED IN DRG NEURONS AFTER REPEATED MORPHINE TREATMENT. DNA METHYLATION IS AN IMPORTANT MECHANISM OF EPIGENETIC CONTROL OF GENE EXPRESSION. IN THE CURRENT STUDY, WE HYPOTHESIZED THAT THE DEMETHYLATION REGULATION OF CERTAIN BDNF GENE PROMOTERS IN DRG NEURONS MAY CONTRIBUTE TO THE DEVELOPMENT OF OIH. REAL-TIME RT-PCR WAS USED TO ASSESS CHANGES IN THE MRNA TRANSCRIPTION LEVELS OF MAJOR BDNF EXONS INCLUDING EXON I, II, IV, VI, AS WELL AS TOTAL BDNF MRNA IN DRGS FROM RATS AFTER REPEATED MORPHINE ADMINISTRATION. THE LEVELS OF EXON IV AND TOTAL BDNF MRNA WERE SIGNIFICANTLY UPREGULATED BY REPEATED MORPHINE ADMINISTRATION, AS COMPARED TO THAT IN SALINE CONTROL GROUP. FURTHER, ELISA ARRAY AND IMMUNOCYTOCHEMISTRY STUDY REVEALED A ROBUST UPREGULATION OF BDNF PROTEIN EXPRESSION IN DRG NEURONS AFTER REPEATED MORPHINE EXPOSURE. CORRESPONDINGLY, THE METHYLATION LEVELS OF BDNF EXON IV PROMOTER SHOWED A SIGNIFICANT DOWNREGULATION BY MORPHINE TREATMENT. IMPORTANTLY, INTRATHECAL ADMINISTRATION OF A BDNF ANTIBODY, BUT NOT CONTROL IGG, SIGNIFICANTLY INHIBITED MECHANICAL HYPERSENSITIVITY THAT DEVELOPED IN RATS AFTER REPEATED MORPHINE TREATMENT. CONVERSELY, INTRATHECAL ADMINISTRATION OF AN INHIBITOR OF DNA METHYLATION, 5-AZA-2'-DEOXYCYTIDINE (5-AZA-DC) MARKEDLY UPREGULATED THE BDNF PROTEIN EXPRESSION IN DRG NEURONS AND ENHANCED THE MECHANICAL ALLODYNIA AFTER REPEATED MORPHINE EXPOSURE. TOGETHER, OUR FINDINGS SUGGEST THAT DEMETHYLATION REGULATION OF BDNF GENE PROMOTER MAY BE IMPLICATED IN THE DEVELOPMENT OF OIH THROUGH EPIGENETIC CONTROL OF BDNF EXPRESSION IN DRG NEURONS.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
18  5267  28 PROMOTER ACTIVITY-BASED CASE-CONTROL ASSOCIATION STUDY ON SLC6A4 HIGHLIGHTING HYPERMETHYLATION AND ALTERED AMYGDALA VOLUME IN MALE PATIENTS WITH SCHIZOPHRENIA. ASSOCIATIONS BETWEEN ALTERED DNA METHYLATION OF THE SEROTONIN TRANSPORTER (5-HTT)-ENCODING GENE SLC6A4 AND EARLY LIFE ADVERSITY, MOOD AND ANXIETY DISORDERS, AND AMYGDALA REACTIVITY HAVE BEEN REPORTED. HOWEVER, FEW STUDIES HAVE EXAMINED EPIGENETIC ALTERATIONS OF SLC6A4 IN SCHIZOPHRENIA (SZ). WE EXAMINED CPG SITES OF SLC6A4, WHOSE DNA METHYLATION LEVELS HAVE BEEN REPORTED TO BE ALTERED IN BIPOLAR DISORDER, USING 3 INDEPENDENT COHORTS OF PATIENTS WITH SZ AND AGE-MATCHED CONTROLS. WE FOUND SIGNIFICANT HYPERMETHYLATION OF A CPG SITE IN SLC6A4 IN MALE PATIENTS WITH SZ IN ALL 3 COHORTS. WE SHOWED THAT CHRONIC ADMINISTRATION OF RISPERIDONE DID NOT AFFECT THE DNA METHYLATION STATUS AT THIS CPG SITE USING COMMON MARMOSETS, AND THAT IN VITRO DNA METHYLATION AT THIS CPG SITE DIMINISHED THE PROMOTER ACTIVITY OF SLC6A4. WE THEN GENOTYPED THE 5-HTT-LINKED POLYMORPHIC REGION (5-HTTLPR) AND INVESTIGATED THE RELATIONSHIP AMONG 5-HTTLPR, DNA METHYLATION, AND AMYGDALA VOLUME USING BRAIN IMAGING DATA. WE FOUND THAT PATIENTS HARBORING LOW-ACTIVITY 5-HTTLPR ALLELES SHOWED HYPERMETHYLATION AND THEY SHOWED A NEGATIVE CORRELATION BETWEEN DNA METHYLATION LEVELS AND LEFT AMYGDALA VOLUMES. THESE RESULTS SUGGEST THAT HYPERMETHYLATION OF THE CPG SITE IN SLC6A4 IS INVOLVED IN THE PATHOPHYSIOLOGY OF SZ, ESPECIALLY IN MALE PATIENTS HARBORING LOW-ACTIVITY 5-HTTLPR ALLELES.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
19  3372  40 HISTONE MODIFICATIONS OF THE CRHR1 GENE IN A RAT MODEL OF DEPRESSION FOLLOWING CHRONIC STRESS. MULTIPLE LINES OF EVIDENCE SUGGEST A LINK BETWEEN DEPRESSION AND CHANGES IN HYPOTHALAMIC-PITUITARY-ADRENAL (HPA)-AXIS HORMONE DYNAMICS, INCLUDING ALTERED REGULATION OF THE CORTICOTROPHIN-RELEASING HORMONE (CRH) AND ITS MAIN RECEPTOR, CORTICOTROPHIN-RELEASING HORMONE RECEPTOR 1 (CRHR1). HOWEVER, THE PRECISE MOLECULAR MECHANISMS UNDERLYING DEPRESSION REMAIN POORLY UNDERSTOOD. IN THIS STUDY, WE EMPLOYED A MODEL OF DEPRESSION IN RATS BY SUBJECTING ANIMALS TO 21 DAYS OF CHRONIC UNPREDICTABLE MILD STRESS (CUMS). REAL-TIME PCR AND WESTERN BLOTTING WERE USED TO STUDY THE MRNA AND PROTEIN EXPRESSION LEVELS OF CRHR1 IN THE HYPOTHALAMUS. IN ADDITION, CHROMATIN IMMUNOPRECIPITATION ASSAYS WERE USED TO DETECT HISTONE METHYLATION AT THE CRHR1 GENE PROMOTER; THE LEVELS OF HISTONE H3 TRIMETHYLATION AT LYSINES 4 (H3K4) AND 9 (H3K9) REFLECT ACTIVE TRANSCRIPTION AND TRANSCRIPTIONAL REPRESSION, RESPECTIVELY. RATS EXPOSED TO CUMS EXHIBITED SIGNIFICANT REDUCTION IN LOCOMOTION AND SUCROSE PREFERENCE. THESE BEHAVIORAL ALTERATIONS WERE ASSOCIATED WITH ELEVATED EXPRESSION LEVELS OF CRHR1 MRNA AND PROTEIN IN THE HYPOTHALAMUS OF RATS IN THE CUMS GROUP. WE ALSO FOUND THAT THE LEVELS OF H3K9 TRIMETHYLATION AT THE CRHR1 GENE PROMOTER IN THE CUMS GROUP WERE SIGNIFICANTLY LOWER THAN THOSE IN THE CONTROL GROUP, WHEREAS H3K4 TRIMETHYLATION LEVELS WERE THE SAME FOR BOTH GROUPS. TAKEN TOGETHER, OUR FINDINGS SUGGEST THAT THE INCREASE IN CRHR1 EXPRESSION IN THE HYPOTHALAMUS OF STRESSED RATS CORRELATES WITH A DECREASE IN THE REPRESSIVE CHROMATIN STATE CAUSED BY REDUCED H3K9 TRIMETHYLATION LEVELS. THESE DATA ARE THE FIRST IN VIVO EVIDENCE OF A ROLE FOR CHROMATIN MODIFICATIONS IN THE REGULATION OF CRHR1 GENE EXPRESSION IN THE HYPOTHALAMUS, AND MAY PROVIDE NOVEL INSIGHT INTO THERAPEUTIC APPROACHES TO TREAT DEPRESSION.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
20  3318  40 HISTONE ACETYLATION AND EXPRESSION OF MONO-AMINERGIC TRANSMITTERS SYNTHETASES INVOLVED IN CUS-INDUCED DEPRESSIVE RATS. HISTONE ACETYLATION HAS BEEN LINKED TO DEPRESSION, THE ETIOLOGY OF WHICH INVOLVES MANY FACTORS SUCH AS GENETICS, ENVIRONMENTS, AND EPIGENETICS. THE AIM OF THE PRESENT STUDY WAS TO INVESTIGATE WHETHER IT WAS ASSOCIATED WITH EPIGENETIC HISTONE MODIFICATION AND GENE EXPRESSION OF ENZYMES RESPONSIBLE FOR THE BIOSYNTHESIS OF NOREPINEPHRINE AND SEROTONIN IN RAT DEPRESSION MODEL INDUCED BY CHRONIC UNPREDICTABLE STRESS (CUS). EIGHT-WEEK-OLD MALE SPRAGUE-DAWLEY RATS WERE EXPOSED TO CUS OVER 28 DAYS. IT WAS SHOWN THAT THE CUS-INDUCED RATS DISPLAYED REMARKED ANXIETY- AND DEPRESSION-LIKE BEHAVIOR WITH WEAKENED LOCOMOTOR ACTIVITY IN OPEN FIELD TEST AND PROLONGED IMMOBILITY IN FORCED SWIMMING TEST. WESTERN BLOT REVEALED THAT CUS LED TO SIGNIFICANT DECREASE IN ACETYLATION OF H3 AT LYSINE 9 (K9) AND H4 AT LYSINE 12 (K12) WITH OBVIOUSLY INCREASING HISTONE DEACETYLASES 5 (HDAC5) EXPRESSION IN HIPPOCAMPUS OF CUS-INDUCED RATS. MEANWHILE, THERE WAS AN OBVIOUSLY DECREASED EXPRESSION OF TYROSINE HYDROXYLASE (TH) AND TRYPTOPHAN HYDROXYLASE (TPH) BOTH AT PROTEIN AND MRNA LEVELS. ADMINISTRATION OF SODIUM VALPROATE (VPA), A HISTONE DEACETYLASE 5 (HDAC5) INHIBITOR, NOT ONLY SIGNIFICANTLY RELIEVED THE ANXIETY- AND DEPRESSION-LIKE BEHAVIORS OF CUS-INDUCED RATS BUT ALSO CLEARLY BLUNTED DECREASE OF H3(K9) AND H4(K12) ACETYLATION AND EXPRESSION OF TH AND TPH, AND PREVENTED INCREASE OF HDAC5 EXPRESSION. THE RESULTS INDICATE THAT THERE EXISTS POSSIBLE INTERRELATION BETWEEN TH AND TPH GENE EXPRESSION AND EPIGENETIC HISTONE ACETYLATION IN CUS-INDUCED DEPRESSIVE RATS, WHICH AT LEAST PARTLY CONTRIBUTES TO THE ETIOLOGY OF DEPRESSION.	2014